Paroxetine has the chemical formula (−)-(3S,4R)-4-(p-fluorophenyl)-3-[(3,4-methylenedioxy)phenoxy]-methyl]piperidine, and is used as a therapeutic agent for the treatment of depression, panic disorder, pre-menstrual dysphoric disorder and social phobia by taking advantage of a typical selective serotonin (5-HT) reuptake inhibitor (SSRI) mechanism.
It is reported that since general anti-depressants, including paroxetine, have poor medication compliance in patients, the development of oral formulations for swallowing without water will improve the medication compliance of patients by decreasing the sensation of medicine administration. According to clinical results of Remeron SolTab (manufactured under the trade name Mirtazapine by Janssen), which is the first developed oral anti-depressant for swallowing without water in the world, continuous treatment of depression without stopping in the initial stage is mentioned as a critical factor in the improvement of symptoms in a depressive patient. A study on patients who had been administered Remeron SolTab reported that the patients preferred SolTab preparations to other conventional pills. This study also reported that the proportion of patients responding the selection of SolTab is six times higher than that responding the selection of other pills. These results reveal that the use of anti-depressants for swallowing without water improves therapeutic compliance in patients and thus better results in the treatment of depression and the prevention of depression recurrence can be expected.
However, paroxetine has a very bitter taste even at low concentrations, whilst it causes irritating pain along with a very bitter taste at high concentrations due to its inherent characteristics. Accordingly, paroxetine is limited in its ability to be developed into solid oral formulations for swallowing without water. Although paroxetine can be coated with or included in materials, such as polymers and cyclodextrins, by common techniques known in the art, the bitter taste of paroxetine is incompletely masked. Particularly, when paroxetine is formulated into a tablet, the shape of the coated or included granule may be partially collapsed to expose the contents to the outside of the granule, which render an uncomfortable sensation in the mouth. In order to wholly or partially block the bitter and irritant taste of paroxetine, the use of excipients in large quantities is necessary. Accordingly, it is substantially impossible to develop an orally disintegrating tablet.
PCT Publication WO 95/020964 discloses a process for formulating a liquid preparation (liquid for medication) by dispersing a water-insoluble ion exchange resin in water and formulating the dispersion with a drug, thereby masking the bitter taste of the drug. However, since the ion exchange resin is insoluble in water, it cannot be uniformly distributed in an aqueous phase and thus the bitter taste of the drug cannot be completely masked.
In efforts for masking the inherent taste of paroxetine with another taste, glycyrrhyzinic acid or glycyrrhyzinate salts are found in PCT Publications WO 03/013470 and WO 03/013529. These publications mention that since glycyrrhyzinate as a main ingredient of liquorice has itself an intense flavor of sweet liquorice, it can contribute to masking the bitter taste of paroxetine. In fact, the abstracts of the publications describe that because of the intensity of liquorice flavor even in a state where glycyrrhyzinate is formulated, further flavorings may be desirable to modify the liquorice taste of the formulation.
A number of studies on salts of paroxetine have been actively undertaken. For example, U.S. Pat. No. 4,721,723 and PCT Publication WO 99/32484 describe paroxetine hydrochloride; PCT Publication WO 99/52901 describes paroxetine maleate; PCT Publication WO 99/55699 describes paroxetine camphorsulfonates; PCT Publication WO 99/55698 describes paroxetine ascorbate; PCT Publication WO 00/01694 describes paroxetine methanesulfonate; PCT Publications WO 03/013470 and WO 03/013529 describe glycyrrhyzinate or glycyrrhyzinate salts; PCT Publication WO 99/40084 describes salts of paroxetine with acids, including sulfuric, tartaric, oxalic, fumaric, propionic, formic, glutamic, succinic, benzoic, citric, nitric, phosphoric, 4-methylbenzenesulfonic, hypophosphorous, lactic, and mandelic acids, without detailed explanations regarding the salts; and PCT Publication WO 00/01692 describes salts of paroxetine with an acid group. However, none of the above patent publications mention an improvement in taste associated with the use of the paroxetine salts.
In addition to these salts of paroxetine, PCT Publication WO 95/20964 claims a liquid oral preparation using a paroxetine-amberlite complex. However, the amberlite resin is not a monomolecular material, but a polymeric material carrying many charges in a single molecule, and is particularly insoluble in water or solvents. The molecular weight of polymers can be expressed only by average molecular weight due to the characteristics of polymers. Accordingly, the binding molar ratio of the amberlite resin to the drug cannot be precisely attained, unlike monomolecular salts, and thus it is difficult to say that the paroxetine-amberlite complex is a salt. In addition, the taste-masking effects of the polymeric resin are due to the dispersion of the water-insoluble resin-drug complex in water. Accordingly, the effects of the complex are distinguished from those of paroxetine salts.
Little has heretofore been reported, suggested, or experimentally proved about the absence of taste and pain of paroxetine, and the greatly improved stability of paroxetine through the formation of paroxetine salts. Particularly, there are no reports about paroxetine cholate and cholic acid derivative salts.
Thus, it is an object of the present invention to provide a paroxetine salt or a paroxetine composition capable of causing changes in the characteristics of paroxetine molecular units to change the taste properties of paroxetine such that the bitter taste of paroxetine, even after it is completely dissolved in water, is removed in the salt or the composition.
It is another object of the present invention to provide a paroxetine oral preparation for swallowing without water, namely an orally disintegrating tablet, comprising the paroxetine salt or the paroxetine composition.